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Pre-filled syringes are becoming more popular as a preferred container closure system for biologics. Pre-filled syringes must offer an inherent barrier that maintains drug product stability and sterility throughout its entire shelf life as a primary container closure system. The ability of the system to retain its microbial barrier integrity must be checked and demonstrated by the drug manufacturers. In 2008, the FDA endorsed CCI testing as part of the sterile product stability protocol.

The pharmaceutical industry has witnessed substantial technical developments in CCI testing in response to rising regulatory demands. MicroCurrent HVLD, Vacuum Decay Leak Testing and Helium Leak Detection are examples of new technologies that have proven enhanced detection capabilities above traditional Dye and Microbial Ingress approaches. Many of the technologies have been employed for CCI testing of drug product stability.

CCI Testing Strategy for Development

Many CCI failure modes can occur throughout the life cycle of a syringe, from component production to drug product filling and sealing, device assembly and packaging, and finally distribution and storage. It is critical to create a comprehensive plan for conducting CCI testing across the whole syringe life cycle.

The creation of the CCI testing technique begins with a detailed study of the construction, design, and manufacturing procedures used in syringes. The failure modes and impacts associated with each aspect of CCI were identified first. The next step was to evaluate whether CCI testing is required, as well as the intended uses and testing frequencies, using a risk-based approach. Knowing that the needle shield compartment seal integrity had been verified by the component supplier, apply a non-routine CCI test to validate its seal integrity during drug product loading and sealing, as well as during device assembly. To ensure CCI was achieved and successfully maintained, implement a complete set of CCI tests across the entire product development cycle for the product-containing syringe barrel compartment.

Method Development and Method Validation

Method development consists of optimizing testing parameters and determining the appropriate pass/fail threshold.

• Testing parameters optimization

Initially, several defect standards of known sizes were examined alongside undamaged samples using varied testing conditions. The relationships between key method parameters and instrument responses to intact and defect samples were comprehensively investigated, with the objective of determining a set of variables that give optimal separation between intact and defect samples. i.e. signal-to-noise ratio or SNR.

• Pass/fail threshold determination

The improved method was utilized to evaluate different lots of filled intact syringes representing relevant product variations, such as drug product batches, and packaging locations and lines, in order to define the preliminary pass/fail threshold. For intact samples, the results of the tests were statistically assessed to determine the instrument baseline and variation (σ). Typically, the pass/fail threshold should be 10 σ higher than baseline. The pass/fail threshold was then further refined and verified by testing defect standards of known sizes.

CCI testing techniques were validated for the pharmaceutical product package. Since the drug product formulation and package design may change during the early development stages, a step-by-step approach was adopted to validate the methods in line with the product development stages. Once product design and packaging design are complete, the methods are fully validated to support CCI testing for initial consistency and process evaluation. The power of the additional long-term method may be further validated before this method is implemented in QC laboratories for routine testing.

During package and pharmaceutical product development and manufacturing, properly selected and verified methodologies are critical for demonstrating container closure integrity. It should be noted that existing CCI testing methods do not provide an optimal solution for all pre-filled syringe CCI testing requirements. To maintain total container closure integrity, an integrated solution involving CCI testing as well as additional engineering and administrative controls is required.